Alzheimer's disease (AD) is characterized by extracellular deposits of beta-protein derived from an amyloid precursor protein (APP) which when mutated at APP717 appears to result in AD. Along with other investigators, we have found two pathways for amyloid precursor degradation, secretion and lysosomal degradation. The lysosomal degradative pathway normally removes potentially amyloidogenic and other C-terminal APP fragments from cultured cells suggesting that a deficiency in this pathway in aging or Alzheimer's disease could promote beta-protein deposition. However, no differences between normal and AD in beta-containing, full-length APP or C-terminal fragments have been found, while there is a suggestion of age changes. APP metabolism is modified by protein kinase C (PK-C) and we have shown altered PK-C in AD. We propose to reexamine the relationship of aging and AD to PK-C and to APP and its metabolites to determine whether age or AD-linked changes actually occur. We have preliminary evidence that specific, age-related, factors can modulate the rate of C-terminal APP degradation, and possibly, secretion-cleavage sites. We propose to test whether these and related factors can modulate the expression of potentially amyloidogenic fragments in cell culture, in particular, in the endosomal lysosomal pathway as suggested by our preliminary data. We propose to examine APP metabolism in a panel of cells transfected to overproduce these factors and to make a related series of neuronal cells. We have demonstrated beta protein toxicity in culture and identified agents which can block this toxicity. We propose to examine these phenomena in relation to APP. These experiments should help identify agents which normally modulate the rate of amyloid production and, appear to offer new directions for treatment and prevention of AD.